Glycosaminoglycan binding and oligomerization are essential for the
            <i>in vivo</i>
            activity of certain chemokines

Proudfoot, Amanda E. I.; Handel, Tracy M.; Johnson, Zoë; Lau, Elaine K.; LiWang, Patricia J.; Clark‐Lewis, Ian; Borlat, Frédéric; Wells, Timothy N.C.; Kosco‐Vilbois, Marie H.

doi:10.1073/pnas.0334864100

Cited by 712 publications

(852 citation statements)

References 26 publications

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“…Many chemokines are known to interact with glycosaminoglycans (GAG), and this interaction is even required for full in vivo activity in certain cases [7,40]. Shedding GAG from the cell surface had a significant effect neither on chemotaxis induced by CCL7 alone at 1 nM (untreated cells mean7SEM: 105731 or enzyme-treated cells: 86742) nor on the synergistic increase in the presence of 1 mM CCL21 (untreated cells: 253745 or enzymetreated cells: 142742).…”

Section: Glycosaminoglycans and Chemokine Complexesmentioning

confidence: 99%

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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The migration of monocytes to sites of inflammation is largely determined by their response to chemokines. Although the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how cells integrate the messages provided by different chemokines that are concomitantly produced in physiological or pathological situations in vivo. We present evidence for one regulatory mechanism of human monocyte trafficking. Monocytes can integrate stimuli provided by inflammatory chemokines in the presence of homeostatic chemokines. In particular, migration and cell responses could occur at much lower concentrations of the CCR2 agonists, in the presence of chemokines (CCL19 and CCL21) that per se do not act on monocytes. Binding studies on CCR2 1 cells showed that CCL19 and CCL21 do not compete with the CCR2 agonist CCL2. Furthermore, the presence of CCL19 or CCL21 could influence the degradation of CCL2 and CCL7 on cells expressing the decoy receptor D6. These findings disclose a new scenario to further comprehend the complexity of chemokinebased monocyte trafficking in a vast variety of human inflammatory disorders.Key words: Chemokine receptors . Chemokines . Monocytes . Synergism IntroductionConcomitant exposure to multiple chemokines, the key controllers of several immune cell functions [1], can result in enhancement of immune responses. Only recently, a broad phenomenon known as ''chemokine synergism'' has been identified [2][3][4][5][6][7][8][9][10]. Cells expressing two or more chemokine receptors, in the presence of the selective agonists, can amplify their response [2][3][4][5][6]11]. The responses mediated by low agonist concentrations can be powerfully enhanced by non-ligand chemokines in cells that do not bear the second chemokine receptor [7][8][9]. Using different biochemical approaches, these studies demonstrated that CC and CXC chemokines form heteromeric complexes, which could endow the agonist with higher activity [7,9,12].Chemokines mediate their effects through interactions with heterotrimeric G-protein-coupled receptors [13][14][15]. Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].Many chemokines, apart from being agonistic for their receptors, were shown to act as natural antagonists on one or several receptors in vitro and in vivo [22]. Naturally occurring N-terminal truncations of chemokines have been identified in vivo [23] and numerous enzymes were shown to generate truncations of chemokines that render them less active or inactive [24,25]. Therefore, there are strong indications that a cell needs to 1118integrate more than one signal provided by its environment and that environmental factors other than agonists might influence their responses.Chemokine production can be either constitutive or triggere...

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Section: Glycosaminoglycans and Chemokine Complexesmentioning

confidence: 99%

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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“…An increasing body of evidence supports the functional importance of chemokine-HS interactions in the process of leukocyte migration from the blood into inflamed tissues (13,(30)(31)(32). Data suggest an involvement of HS in the transcytosis of chemokines across endothelial cells.…”

mentioning

confidence: 98%

“…This results in leukocyte activation and migration across the endothelium and into the tissue. The functional importance of chemokine-HS interactions has been shown in vivo, because administration of modified chemokines that exhibit reduced affinity to HS or heparin resulted in diminished leukocyte recruitment (31,32). Other functions of glycosaminoglycan-chemokine interactions have been proposed, including the formation of immobilized chemokine gradients in the extracellular matrix and the protection of these mediators from degradation, resulting in the prolongation of their activities (15,35,36).…”

mentioning

confidence: 99%

Induction of a CXCL8 binding site on endothelial syndecan‐3 in rheumatoid synovium

Patterson

Gardner

Shaw

et al. 2005

Arthritis & Rheumatism

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“…As mentioned above, chemokine activity in vivo was shown to be dependent on the interaction with glycosaminoglycans (GAGs) [2]. This means, that only the triple complex consisting of chemokine, chemokine-specific GPC receptor, and GAG co-receptor gives the fully functional entity for chemotaxis in vivo.…”

Section: Ms Is An Inflammatory Disease Of the Central Nervous System mentioning

confidence: 99%

“…Bound to glycosaminoglycans (GAGs, see below) on the endothelium, chemokines are retained at the site of action and are presented in their active conformation towards the attracted leukocytes [2]. Once activated via chemokine-specific GPCRs, the target blood cells migrate through the endothelial blood vessel cell layer to enter the site of tissue inflammation and to further induce and to boost the host immune response [3].…”

Section: Introductionmentioning

confidence: 99%